This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Liposomes are nano-size carriers that have been effectively applied for drug and gene delivery for therapeutic purposes. Their successful application requires good knowledge of the molecular mechanisms of uptake and subsequent drug release. Lipid phase state is a key physical attribute because it affects virtually all properties of lipid dispersions. This project is focused on the further exploration of the relationship between lipid phase behavior and transfection efficacy. It is predicated on the hypothesis that a key factor for DNA delivery is the structural evolution of the lipoplexes upon internalization and interaction with cellular lipids. The specific aims are: 1) to correlate the cationic lipids chemical structure, their phase behavior in mixed formulations, their interactions with cellular lipids, and their efficiency in delivering DNA for transfection;2) to formulate lipoplexes of predicted superiority for facilitating DNA release and improving transfection efficacy.